BY ANTHONY KING
Lipid nanoparticles (LNPs) have been designed to cross into the brain of mice to deliver mRNA. Researchers at the University of Pennsylvania relied on LNPs fitted with special targeting peptides to successfully ferry mRNA into neurons (Nano Letters, DOI: 10.1021/acs.nanolett.4c05186).
This approach could deliver therapeutics across the blood-brain barrier (BBB) for neurological conditions, perhaps Parkinson’s and Alzheimer’s disease. ‘LNPs are a nice platform because we can modify them and put targeting groups like peptides on their surface,’ says lead author Emily Han.
LNPs gained widespread attention after being used to deliver mRNA for the Covid-19 vaccines from Moderna and Pfizer. However, most LNPs naturally end up in the liver when administered intravenously, not the brain.
Raising the bar further for brain treatments, the BBB stops around 98% of small molecule drugs and almost all large molecule drugs, including mRNA, from entering the brain. Early in 2024, Han and colleagues screened LNPs for their ability to cross the BBB and deliver mRNA to the endothelial cells that line the barrier (Nano Letters, DOI: 10.1021/acs.nanolett.3c03509).
‘We delivered mRNA into the brain, but we didn’t know to which cell types,’ says Han. For the second study, the lab chose four peptides (RVG29, T7, AP2, and mApoE) that target receptors that are abundant on brain endothelial cells and neurons.
Compared with traditional targeting ligands, such as antibodies, peptides are smaller and can fit easier onto LNPs, without risking the particle getting too large or aggregating. The strategy requires barrier cells to pull the LNP inside it, so it can transit to the other side inside cell packaging structures called endosomes.
‘LNPs are unique because they have this ionisable lipid, which means it changes structure depending on the pH,’ Han explains. ‘Endosomes of cells have really low pH, so that causes the ionisable lipid to become positively charged, disrupting the negative endosomal membrane, so that the cargo of the LNP can be released.’
The experiments were done in healthy mice; the hope now is that the lab, headed by Michael Mitchell, can collaborate with companies or other labs interested in treating brain conditions. ‘This is a very important paper by Mitchell and his team,’ says Robert Langer, Professor of biotechnology at Massachusetts Institute of Technology, US. It could open up the possibility of someday treating brain diseases – of which there are many – with messenger RNA.’
For now, only a small fraction of the LNP reached the brains of the mice. ‘We report hitting about 1 to 2% of neurons in a mouse brain. We’re not sure if this is therapeutically relevant and we may need to scale up the dose for larger animals and then recheck toxicity,’ says Han.
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